A New Diagnostic Biomarker for Multiple Sclerosis Patients: Endocan Level

Abstract

Objective: Multiple sclerosis (MS) is an immune-mediated demyelinating disease affecting the human central nervous system. Many molecules are involved in its pathophysiology and help determine prognosis. The goal of this study was to determine serum endocan levels in patients with inactive MS. Methods: A total of 96 participants were included in the study; 48 patients with relapsing-remitting MS (mean age: 37.46±12.53, 20 men/28 women) and 48 controls (mean age: 38.22±18.57, 22 men/26 women). After the samples were thawed under appropriate conditions, serum endocan levels were analyzed by enzyme-linked immunosorbent assay. The relationship between endocan levels and the Expanded Disability Status Scale, demographic characteristics and medications were analyzed. Results: The endocan concentration was 371.04±67.39 ng/l in patients with MS and 1003.78±110.63 ng/l in the controls. Patients with MS had significantly lower levels of endocan than the controls did (P=.003). Endokan had the lowest diagnostic value (AUC=0.67, (95% CI, 0.56-0.78) as the cut-off value (229.50), sensitivity (63.04%) and specifity (39.13%) in the MS group. In this study, no significant differences were detected between Endocan and the other clinical parameters. Conclusion: According to the results of our study, compared withthose in healthy patients, endocan levels in MS patients were lower. It was concluded that the edokan level can be used as a biomarker in MS patients.

Keywords

• Diagnostic biomarker
• EDSS
• endocan
• inflammation
• multiple sclerosis

Multipl Skleroz Hastalarında Yeni Bir Tanısal Biyobelirteç: Endokan Düzeyi

Öz

Amaç: Multipl skleroz (MS), insan merkezi sinir sistemini etkileyen, immün aracılı demiyelinizan bir hastalıktır. Patofizyolojisinde rol alan ve prognozun belirlenmesine yardımcı olan birçok molekül bulunmaktadır. Bu çalışmanın amacı, inaktif MS hastalarında serum endokan düzeyini ve bunun patogenezdeki rolünü belirlemektir. Yöntemler: Çalışmaya toplam 96 katılımcı dâhil edildi; bunların 48’i relapsing-remitting MS hastası (ortalama yaş: 37,46±12,53; 20 erkek/28 kadın) ve 48’i kontrol grubuydu (ortalama yaş: 38,22±18,57; 22 erkek/26 kadın). Uygun koşullar altında çözdürüldükten sonra serum endokan düzeyleri, enzim bağlı immünosorbent analiz (ELISA) yöntemi ile analiz edildi. Endokan düzeyleri ile Genişletilmiş Özürlülük Durum Ölçeği (EDSS), demografik özellikler ve kullanılan ilaçlar arasındaki ilişki değerlendirildi. Bulgular: Endokan düzeyleri MS hastalarında 371,044±67,396 ng/L, kontrol grubunda ise 1003,783±110,634 ng/L olarak ölçüldü. MS hastalarında endokan düzeyleri kontrol grubuna göre anlamlı derecede daha düşüktü (P=,003). Endokan için tanısal değer; eğri altındaki alan (AUC)=0,677 (%95 GA: 0,567–0,787), kesim değeri 229,500, duyarlılık %63,04 ve özgüllük %39,13 olarak saptandı. Çalışmada endokan ile diğer klinik parametreler arasında anlamlı bir fark bulunmadı. Sonuç: Çalışmamızın sonuçlarına göre, MS hastalarında sağlıklı gruba kıyasla endokan düzeylerinde azalma olduğu gözlenmiştir. Endokan düzeyinin MS hastalarında bir biyobelirteç olarak kullanılabileceği sonucuna varılmıştır.

Anahtar Kelimeler

• Tanısal biyobelirteç
• EDSS
• endokan
• inflamasyon
• multipl skleroz

Kaynakça

1. 1. Walton C, King R, Rechtman L, et al. Rising prevalence of multiple sclerosis worldwide: insights from the Atlas of MS, third edition. Mult Scler. 2020;26:1816-1821.
2. 2. Lassmann H, Brück W, Lucchinetti CF. The immunopathology of multiple sclerosis: an overview. Brain Pathol. 2007;17:210-218.
3. 3. Baecher-Allan C, Kaskow BJ, Weiner HL. Multiple sclerosis: mechanisms and immunotherapy. Neuron. 2018;97:742-768.
4. 4. Kaisey M, Solomon AJ, Luu M, Giesser BS, Sicotte NL. Incidence of multiple sclerosis misdiagnosis in referrals to two academic centers. Mult Scler Relat Disord. 2019;30:51-56.
5. 5. Kelly SB, Chaila E, Kinsella K, et al. Multiple sclerosis, from referral to confirmed diagnosis: an audit of clinical practice. Mult Scler. 2011;17:1017-1021.
6. 6. Dendrou CA, Fugger L, Friese MA. Immunopathology of multiple sclerosis. Nat Rev Immunol. 2015;15:545-558.
7. 7. Nylander A, Hafler DA. Multiple sclerosis. J Clin Invest. 2012;122:1180-1188.
8. 8. Göbel K, Ruck T, Meuth SG. Cytokine signaling in multiple sclerosis: lost in translation. Mult Scler. 2018;24:432-439.

9. 9. Su JJ, Osoegawa M, Matsuoka T, et al. Upregulation of vascular growth factors in multiple sclerosis: correlation with MRI findings. J Neurol Sci. 2006;243:21-30.
10. 10. Kuhle J, Malmeström C, Axelsson M, et al. Neurofilament light and heavy subunits compared as therapeutic biomarkers in multiple sclerosis. Acta Neurol Scand. 2013;128:e33-e36.
11. 11. Sarrazin S, Lyon M, Deakin JA, et al. Characterization and binding activity of the chondroitin/dermatan sulfate chain from Endocan, a soluble endothelial proteoglycan. Glycobiology. 2010;20:1380-1388.
12. 12. Béchard D, Gentina T, Delehedde M, et al. Endocan is a novel chondroitin sulfate/dermatan sulfate proteoglycan that promotes hepatocyte growth factor/scatter factor mitogenic activity. J Biol Chem. 2001;276:48341-48349.
13. 13. Sarrazin S, Adam E, Lyon M, et al. Endocan or endothelial cell-specific molecule-1 (ESM-1): a potential novel endothelial cell marker and a new target for cancer therapy. Biochim Biophys Acta. 2006;1765:25-37.
14. 14. Scherpereel A, Depontieu F, Grigoriu B, et al. Endocan, a new endothelial marker in human sepsis. Crit Care Med. 2006;34:532-537.
15. 15. Gaudet A, Chenevier-Gobeaux C, Parmentier E, et al. Endocan is a stable circulating molecule in ICU patients. Clin Biochem. 2017;50:870-877.
16. 16. Béchard D, Meignin V, Scherpereel A, et al. Characterization of the secreted form of endothelial-cell-specific molecule 1 by specific monoclonal antibodies. J Vasc Res. 2000;37:417-425.
17. 17. Caires NDF, Legendre B, Parmentier E, et al. Identification of a 14 kDa endocan fragment generated by cathepsin G, a novel circulating biomarker in patients with sepsis. J Pharm Biomed Anal. 2013;78-79:45-51.
18. 18. Bouglé A, Allain PA, Favard S, et al. Postoperative serum levels of Endocan are associated with the duration of norepinephrine support after coronary artery bypass surgery. Anaesth Crit Care Pain Med. 2018;37:656-570.
19. 19. Varan HD, Guner G, Kizilarslanoglu MC, et al. Higher serum endocan level is associated with Alzheimer disease. Dement Geriatr Cogn Disord. 2017;44:303-310.
20. 20. Aciksari G, Kavas M, Atici A, et al. Endocan levels and endothelial dysfunction in patients with sarcoidosis. Angiology. 2018;69:878-883.
21. 21. Atukeren P, Kunbaz A, Turk O, et al. Expressions of endocan in patients with meningiomas and gliomas. Dis Markers. 2016;2016:7157039.
22. 22. Yilmaz Y, Berru Durmuş R, Saraçoğlu B, et al. The assessment of serum endocan levels in children with juvenile idiopathic arthritis. Arch Rheumatol. 2017;33:168-173.
23. 23. Van Oosten BW, Barkhof F, Scholten PE, et al. Increased production of tumor necrosis factor alpha, and not of interferon gamma, preceding disease activity in patients with multiple sclerosis. Arch Neurol. 1998;55:793-798.
24. 24. Yoon KH, Kim SY, Moon YS, Roh D, Lee SK, Kim DH. The relationship between serum endocan levels and depression in Alzheimer’s disease. Dis Markers. 2016;2016:8254675.
25. 25. Kealy J, Greene C, Campbell M. Blood-brain barrier regulation in psychiatric disorders. Neurosci Lett. 2020;726:133664.
26. 26. Akil E, Alp R, Aluclu MU, Acar A, Kaplan I. Serum endocan levels in multiple sclerosis relapse and remission. Eur Rev Med Pharmacol Sci. 2021;25(11):4091-4098.
27. 27. Atalar AC, Köseoğlu M, Yavuz N, Erdal Y, Oğuz O, Emre U. Could serum endocan be a vascular endothelial marker in relapsing-remitting multiple sclerosis? Turk J Neurol. 2021;27:257-262.
28. 28. Nakamura T, Mizuno S. The discovery of hepatocyte growth factor (HGF) and its significance for cell biology, life sciences and clinical medicine. Proc Jpn Acad Ser B Phys Biol Sci. 2010;86:588-610.
29. 29. Maina F, Klein R. Hepatocyte growth factor, a versatile signal for developing neurons. Nat Neurosci. 1999;2:213-217.
30. 30. Benkhoucha M, Santiago-Raber ML, Schneiter G, et al. Hepatocyte growth factor inhibits CNS autoimmunity by inducing tolerogenic dendritic cells and CD25+Foxp3+ regulatory T cells. Proc Natl Acad Sci U S A. 2010;107:6424-6429.
31. 31. Lalive PH, Paglinawan R, Biollaz G, et al. TGF-beta-treated microglia induce oligodendrocyte precursor cell chemotaxis through the HGF-c-Met pathway. Eur J Immunol. 2005;35:727-737.
32. 32. Kitamura K, Iwanami A, Nakamura M, et al. Hepatocyte growth factor promotes endogenous repair and functional recovery after spinal cord injury. J Neurosci Res. 2007;85:2332-2342.
33. 33. Rocha SF, Schiller M, Jing D, et al. Esm1 modulates endothelial tip cell behavior and vascular permeability by enhancing VEGF bioavailability. Circ Res. 2014;115:581-590.
34. 34. Zhang X, Zhuang R, Wu H, et al. A novel role of endocan in alleviating LPS-induced acute lung injury. Life Sci. 2018;202:89-97.
35. 35. Béchard D, Gentina T, Delehedde M, et al. Endocan is a novel chondroitin sulfate/dermatan sulfate proteoglycan that promotes hepatocyte growth factor/scatter factor mitogenic activity. J Biol Chem. 2001;276(51):48341-48349.
36. 36. Delehedde M, Devenyns L, Maurage CA, et al. Endocan in cancers: a lesson from a circulating dermatan sulfate proteoglycan. Int J Cell Biol. 2013;2013:705027.
37. 37. Kul A, Ateş O, Melikoğlu MA, et al. Endocan measurement for active Behçet disease. Arch Rheumatol. 2017;32:197-202.
38. 38. Iacobaeus E, Amoudruz P, Ström M, et al. The expression of VEGF-A is down regulated in peripheral blood mononuclear cells of patients with secondary progressive multiple sclerosis. PLoS One. 2011;6:e19138.
39. 39. Ruiz de Almodovar C, Lambrechts D, Mazzone M, et al. Role and therapeutic potential of VEGF in the nervous system. Physiol Rev. 2009;89:607-648.
40. 40. Nikolenko VN, Oganesyan MV, Vovkogon AD, et al. Current understanding of central nervous system drainage systems: implications in the context of neurodegenerative diseases. Curr Neuropharmacol. 2020;18:1054-1063.